The invariant chain is required for intracellular transport and function of major histocompatibility complex class II molecules.

Elliott, Eileen A.; Drake, James R.; Amigorena, Sébastian; Elsemore, Jennifer; Webster, Paul; Mellman, Ira; Flavell, Richard A.

doi:10.1084/jem.179.2.681

Cited by 173 publications

(101 citation statements)

References 54 publications

(100 reference statements)

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“…All experimental procedures were approved by the Animal Care and Use Committee of the local authorities (TV11311A4, AC, LANUV NRW, Essen, Germany). Primary cultures of cardiac fibroblasts were generated from the heart of 1‐ to 7‐day‐old wild‐type (WT; C57Bl/6J) mice (Charles‐River Laboratories, Sulzfeld, Germany) or CD74 knockout (B6‐(Cd74)tm) mice 45. Mice were fed normal chow diets and housed under standardized light‐dark cycles and specific pathogen‐free conditions.…”

Section: Methodsmentioning

confidence: 99%

Soluble CD74 Reroutes MIF/CXCR4/AKT‐Mediated Survival of Cardiac Myofibroblasts to Necroptosis

Soppert

Kraemer

Beckers

et al. 2018

JAHA

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BackgroundAlthough macrophage migration inhibitory factor (MIF) has been demonstrated to mediate cardioprotection in ischemia/reperfusion injury and antagonize fibrotic effects through its receptor, CD74, the function of the soluble CD74 receptor ectodomain (sCD74) and its interaction with circulating MIF have not been explored in cardiac disease.Methods and ResultsCardiac fibroblasts were isolated from hearts of neonatal mice and differentiated into myofibroblasts. Co‐treatment with recombinant MIF and sCD74 induced cell death (P<0.001), which was mediated by receptor‐interacting serine/threonine‐protein kinase (RIP)1/RIP3‐dependent necroptosis (P=0.0376). This effect was specific for cardiac fibroblasts and did not affect cardiomyocytes. Gene expression analyses using microarray and RT‐qPCR technology revealed a 4‐fold upregulation of several interferon‐induced genes upon co‐treatment of myofibroblasts with sCD74 and MIF (Ifi44: P=0.011; Irg1: P=0.022; Clec4e: P=0.011). Furthermore, Western blot analysis confirmed the role of sCD74 as a modulator of MIF signaling by diminishing MIF‐mediated protein kinase B (AKT) activation (P=0.0197) and triggering p38 activation (P=0.0641). We obtained evidence that sCD74 inhibits MIF‐mediated survival pathway through the C‐X‐C chemokine receptor 4/AKT axis, enabling the induction of CD74‐dependent necroptotic processes in cardiac myofibroblasts. Preliminary clinical data revealed a lowered sCD74/MIF ratio in heart failure patients (17.47±10.09 versus 1.413±0.6244).ConclusionsThese findings suggest that treatment of cardiac myofibroblasts with sCD74 and MIF induces necroptosis, offering new insights into the mechanism of myofibroblast depletion during scar maturation. Preliminary clinical data provided first evidence about a clinical relevance of the sCD74/MIF axis in heart failure, suggesting that these proteins may be a promising target to modulate cardiac remodeling and disease progression in heart failure.

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Section: Methodsmentioning

confidence: 99%

Soluble CD74 Reroutes MIF/CXCR4/AKT‐Mediated Survival of Cardiac Myofibroblasts to Necroptosis

Soppert

Kraemer

Beckers

et al. 2018

JAHA

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“…Ii is crucial for proper trafficking of class II molecules to peptide-loading compartments (25). DM plays a critical role in stable peptide binding by class II molecules, while DO is thought to play an inhibitory role, but has not been found to be expressed 3.…”

Section: Gm-csf Increases Total Protein Levels Of Dr Dm II and Do␣mentioning

confidence: 99%

Regulation of the Class II MHC Pathway in Primary Human Monocytes by Granulocyte-Macrophage Colony-Stimulating Factor

Hornell

Beresford

Bushey

et al. 2003

The Journal of Immunology

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GM-CSF stimulates the growth and differentiation of hematopoietic progenitors and also affects mature cell function. These effects have led to the use of GM-CSF as a vaccine adjuvant with promising results; however, the mechanisms underlying GM-CSF-mediated immune potentiation are incompletely understood. In this study, we investigated the hypothesis that the immune stimulatory role of GM-CSF is in part due to effects on class II MHC Ag presentation. We find that, in primary human monocytes treated for 24–48 h, GM-CSF increases surface class II MHC expression and decreases the relative level of the invariant chain-derived peptide, CLIP, bound to surface class II molecules. GM-CSF also increases expression of the costimulatory molecules CD86 and CD40, but not the differentiation marker CD1a or CD16. Furthermore, GM-CSF-treated monocytes are better stimulators in a mixed leukocyte reaction. Additional analyses of the class II pathway revealed that GM-CSF increases total protein and RNA levels of HLA-DR, DM, and DOα. Expression of class II transactivator (CIITA) types I and III, but not IV, transcripts increases in response to GM-CSF. Furthermore, GM-CSF increases the amount of CIITA associated with the DR promoter. Thus, our data argue that the proinflammatory role of GM-CSF is mediated in part through increased expression of key molecules involved in the class II MHC pathway via induction of CIITA.

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“…These clonal hybrids (nearly 500) were then tested for reactivity with APC from wild-type B6, H2-DM-deficient, Ii-deficient, A b EpIi Ϫ , and MHC class II-deficient mice (all from the H2 b haplotype). MHC class II molecules in these mice display varying degrees of class II cell-surface expression levels and peptide diversity: in B6 mice A b class II molecules are bound by a wide gemish of self-peptides; in H2-DM-deficient mice, A b molecules are expressed at normal levels and are mostly bound by a peptide, CLIP, derived from the MHC class II-associated Ii chain (41, 43, 44), but some contamination by non-CLIP peptides has been noted (45,46); in Ii-deficient mice, A b surface expression is reduced ϳ10-fold, and these molecules are thought to be occupied by low-affinity peptides (40,(47)(48)(49); in A b EpIi Ϫ mice, A b surface expression is reduced ϳ10-fold, and these complexes are bound by Ep (7); finally, MHC class II-deficient mice lack class II surface expression altogether (42,50). The reactivity of these hybrids was graded strong, weak, or none, when IL-2 produced by the hybrids was Ͼ50, 10 -50, or Ͻ10%, respectively, of the IL-2 produced when the hybrids were stimulated with wild-type B6 cells (Table I).…”

Section: Few H2-a B -Specific Alloreactive Cd4 ϩ T Cells Recognize Apmentioning

confidence: 99%

The Alloreactive and Self-Restricted CD4+ T Cell Response Directed Against a Single MHC Class II/Peptide Combination

Kovalik

Singh

Mendiratta

et al. 2000

The Journal of Immunology

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The cellular basis for allograft rejection derives from the strong T cell response to cells bearing foreign MHC. While it was originally assumed that alloreactive T cells focus their recognition on the polymorphic residues that differ between syngeneic and allogeneic MHC molecules, studies with MHC class I-restricted CTL have shown that MHC-bound peptides play a critical role in allorecognition. It has been suggested that alloreactive T cells depend more strongly on interactions with the MHC molecule than with the associated peptide, but there is little evidence to support this idea. Here we have studied the alloreactive and self-restricted response directed against the class II H2-Ab molecule bound with a single peptide, Ep, derived from the H2-Eα chain. This MHC class II-peptide combination was a poor target and stimulator of alloreactive CD4+ T cell responses, indicating that MHC-bound peptides are as important for alloreactive CD4+ T cells as they are for alloreactive CTL. We also generated alloreactive T cells with exquisite specificity for the Ab/Ep complex, and compared their reactivity with self-restricted T cells specific for the same Ab/Ep complex. Our results showed that peptide-specific alloreactive T cells, as compared with self-restricted T cells, were more sensitive to peptide stimulation, but equally sensitive to amino acid substitutions in the peptide. These findings indicate that alloreactive and self-restricted T cells interact similarly with their MHC/peptide ligand.

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The invariant chain is required for intracellular transport and function of major histocompatibility complex class II molecules.

Cited by 173 publications

References 54 publications

Soluble CD74 Reroutes MIF/CXCR4/AKT‐Mediated Survival of Cardiac Myofibroblasts to Necroptosis

Soluble CD74 Reroutes MIF/CXCR4/AKT‐Mediated Survival of Cardiac Myofibroblasts to Necroptosis

Regulation of the Class II MHC Pathway in Primary Human Monocytes by Granulocyte-Macrophage Colony-Stimulating Factor

The Alloreactive and Self-Restricted CD4+ T Cell Response Directed Against a Single MHC Class II/Peptide Combination

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